Is lobectomy superior to sub-lobectomy in non-small cell lung cancer with pleural invasion? A population-based competing risk analysis

Background Pleural invasion (PL) has been regarded as an unfavorable prognostic factor for non-small cell lung cancer (NSCLC). But there was no agreement on the optimal surgical extent in NSCLC patients with PL. We aimed to compare the survival outcomes of lobectomy and sub-lobectomy in these patients. Method 2717 patients were included in the Surveillance, Epidemiology, and End Results (SEER) database and divided into the lobectomy and sub-lobectomy groups. The propensity score matching (PSM) and competing risk analysis were implemented. Then the predictive nomogram was constructed and validated. Results 2230 Patients received lobectomy while the other 487 patients underwent sub-lobectomy. After 1:1 PSM, the cumulative incidence of cancer-specific death (CSD) was lower in the lobectomy group compared with the sub-lobectomy group (1-year: 12% vs. 15%; 3-year: 30% vs. 37%, 5-year: 34% vs. 45%, P = 0.04). According to the subgroup analysis, the patients who underwent lobectomy suffered lower CSD in the N0–1 stage, adenocarcinoma, and PL-2 cohort (p < 0.05). And there was a significant relationship between the sub-lobectomy group and CSD in the multivariate competing risks regression analysis (HR, 1.26; 95%CI, 1.02–1.56; P = 0.034). Furthermore, a competing event nomogram was constructed to assess the 1-, 3-, and 5-year chances of CSD based on the variables from the multivariate analysis. The 1-, 3-, 5-year area under the receiver operating characteristic curve (AUC) values were 0.720, 0.706, and 0.708 in the training cohort, and 0.738, 0.696, 0.680 in the validation cohorts, respectively. And calibration curves demonstrated ideal consistency between the predicted and observed probabilities of CSD. Conclusion Lobectomy should be considered the preferred surgery compared to sub-lobectomy for NSCLC patients with PL. The proposed nomograms presented great prediction ability for these patients. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09634-w.


Introduction
Lung cancer is the leading cause of cancer mortality among malignant tumors [1]. Among the common subtypes of lung cancer, non-small cell lung cancer (NSCLC) represents approximately 85% of the overall patients [2], with a 5-year relative survival rate to be 12-15% [3]. Pleural invasion (PL), defined as tumor invasion beyond the elastic layer, has been identified as an independent pathological feature associated with more aggressive biological behavior [4,5]. Previous studies demonstrated that NSCLC patients with PL suffered a higher incidence of poor tumor differentiation, mediastinal lymph node metastatic spread, postoperative recurrence, and poor survival [6][7][8][9].
Lobectomy (Lob) and sub-lobectomy (Sub-lob), the most commonly adopted surgical methods, are the preferred treatment for lung cancer [10]. Lob and systematic lymph node dissection are the gold standard treatment modalities for early-stage NSCLC, which provide more aggressive and comprehensive excision. And Sub-lob presents superiority in patients with significant comorbidities or limited pulmonary function which may be technically easier and carry fewer perioperative complications [11]. As one of the essential elements regarding NSCLC staging, PL directly affects the surgical strategies and prognosis judgment in lung cancer [12]. However, there is no agreement on the optimal surgical extent for NSCLC with PL. Wo et al. [13] and Yu et al. [14] analyzed the prognostic value of surgical extent in NSCLC patients with PL based on the SEER database, indicating that patients who underwent Sub-lob had shorter survival times than those who underwent Lob. Conversely, Moon et al. [15] investigated the surgical outcomes of 271 NSCLC patients with PL and revealed that survival rate did not differ significantly by surgical extent. Thus, controversy still exists regarding the better surgery type (Lob or Sub-lob) in these patients.
Hence, this retrospective study aimed to use the Surveillance, Epidemiology, and End Results (SEER) database to compare the survival outcomes of Lob and Sub-lob in NSCLC patients with PL and construct a predictive nomogram.

Data source and patient selection
Patients were extracted from the SEER 18 regions database [Incidence-SEER Research Plus data, 18  The exclusion criteria were: (1) patients who survived less than 1 month; (2) more than one malignancy; (3) patients with incomplete demographic, clinic-pathological, treatment, and follow-up information. Ultimately, 2717 cases were included in the study. All patients were first divided into Lob and Sub-lob cohorts to perform competing risk analyses. Then the same population was split into training and validation groups to construct a predictive nomogram. The detailed patient selection workflow is shown in Fig. 1.

Clinicopathological variables
Demographic data (year of diagnosis, age, gender, race, marital status), grade, T stage, N stage, metastasis, pathology, pleural invasion, primary site, laterality, tumor size, radiation, chemotherapy, and prognostic information were retrieved from the SEER data repository. The NSCLC patients were reclassified according to the 8th edition TNM classification based on the 7th edition recorded in the SEER database. PL status was obtained from the variables of collaborative stage site-specific factor 2 (2004+) for lung cancer: tumor invasion beyond the visceral elastic layer (PL-1); tumor invasion to the visceral layer (PL-2); tumor extends to the parietal pleura (PL-3). PL-0 and unspecified pleural invasion were excluded based on the research purpose.

Statistical analysis
Continuous variables were expressed as means and standard deviations, and categorical data were summarized as frequency counts and percentages. Differences in the baseline clinicopathological variables were tested using t-test and chi-square test.
All patients were split into Lob and Sub-lob cohorts in the competing risk analyses. OCD (other causes of death) was regarded as an event competing with CSD (cancerspecific death). The endpoints of interest were divided into alive, CSD, and OCD. The cumulative incidence function (CIF) was used for univariate analyses, then the intergroup difference in the CIF was identified by Gray's test. For the multivariate analysis, Fine and Gray's proportional subdistribution hazard model was further used to determine the prognostic factors with the R package "cmprsk" [16].
Using a one-to-one nearest-neighbor algorithm, the propensity score matching (PSM) method was a novel statistical method that could minimize the heterogeneity and mimic randomized controlled trials [17]. We used standardized difference (SD) to present the change of variables before and after PSM. SD ≤0.1 indicated ideal balances in the baseline parameters [18].
Then the overall patients were randomly divided into a training group (70%, n = 1902) and a validation group (30%, n = 815). The prognostic factors identified in the competing risk model were applied to construct a 1-, 3-, and 5-year CSD nomogram in the training dataset. The detailed process was based on the step-by-step method provided by Zhang et al. [19]. The performance of the nomogram was first tested in the training group and subsequently in the validation group by the area under the receiver operating characteristic curve (AUC) values and calibration curves. 1000 bootstrap resamples were used to analyze the expected and observed survival probabilities in the calibration curves. The receiver operating characteristic (ROC) curves were also shown to highlight the built model's prediction power and calculate AUC.
All statistical analyses and visualization were based on R software (version 4.0.3, The R Foundation for Statistical Computing, Vienna, Austria; http:// www.r-proje ct. org). A two-tailed P < 0.05 was indicated to be statistically significant.

Clinicopathological characteristics
2717 patients were finally recruited in the SEER database from 2010 to 2015. Of the overall patients, 2230 (82.08%) and 487 (17.92%) underwent Lob and Sub-lob, respectively. There were significant dissimilarities among the two cohorts in the characteristics, including age, marital status, laterality, T stage, N stage, metastasis, tumor size, radiation, and chemotherapy (all p < 0.05). The patients underwent Lob tended to present higher proportion of married status (60.0% vs. 53.2%), T3 stage (33.3% vs. 21 Given unmatched parameters between the two cohorts, we performed 1:1 PSM to reduce the influence of potential confounders. After PSM, SD in most variables was less than 0.1, which indicated good balancing performance (Fig. S1). Ultimately, 856 patients were separated into the Lob group (n = 428) and Sub-lob group (n = 428). The baseline characteristics before and after PSM are presented in Table 1.

Univariate and multivariate analysis
Then we conducted a second independent analysis. Aiming to construct a prognostic model, we randomly divided the overall patients into a training group (70%, n = 1902) and a validation group (30%, n = 815). There was no significant discrepancy in clinical baselines between the two groups (Table S2). Univariate analyses were used to calculate the 1-, 3-, and 5-year CIF values of CSD in the training cohort. The result revealed that age, gender, grade, T stage, N stage, metastasis, pathology, pleural invasion, primary site, laterality, tumor size, radiation, chemotherapy, and surgery were significantly related to CSD. We did not incorporate tumor size in further analyses because the variable T stage contained tumor size information. Then the significant variables (P < 0.1) were further identified by the multivariate assessment of the Fine-Gray proportional subdistribution hazards model. The multivariate competing risk analysis indicated that age, gender, grade, T stage, N stage, metastasis, pleural invasion, surgery, radiation, and chemotherapy were independent predictors affecting CSD in NSCLC patients with PL (Table 4).

Constructing and verifying the nomogram
A competing event nomogram was constructed to assess the 1-, 3-, and 5-year chances of CSD based on the variables from the multivariate analysis (Fig. 3). The total points were calculated by adding the scores for each patient's prognostic characteristics, which clinicians can use to estimate the chance of CSD at different time points for specific patients.  The nomogram constructed using the training cohort was verified using the validation cohort. The 1-, 3-, 5-year AUC values were 0.720, 0.706, and 0.708 in the training cohort, and 0.738, 0.696, and 0.680 in the validation cohorts, respectively, which indicated good discrimination ability (Fig. 4A and B). We also used calibration plots to test the model's prediction accuracy, which demonstrated relatively good consistency between the predicted and observed probabilities of CSD in both datasets ( Fig. 4C and D). The above results illustrated the good predictive potential along with the high credibility of our nomogram.

Discussion
The study demonstrated that in NSCLC patients diagnosed with PL, the cohort who underwent Lob presented lower CSD than the Sub-lob cohort. The use of a competing risk model could effectively eliminate the influence of death competition on cancer-specific survival, which indicated that these specific patients could obtain better survival from Lob. A competing event nomogram was constructed to individually predict the 1-, 3-, and 5-year chances of CSD among these patients. The model incorporating age, gender, grade, T stage, N stage, metastasis, pleural invasion, surgery, radiation, and chemotherapy presented favorable clinical applicability. To the best of our knowledge, this is the first study to compare Lob and Sub-lob in NSCLC patients with PL and construct a predictive nomogram.
PL is closely related to the aggressive biological behavior of pleural effusion, poor tumor differentiation, lymph node metastasis, postoperative recurrence, and even a dismal prognosis, which can directly affect the surgical strategies [4,5]. Nowadays, Lob and Sub-lob are the most commonly adopted surgical methods for NSCLC [20]. However, there is no agreement regarding the better surgery type (Lob or Sub-lob) in NSCLC patients with PL. Several previous studies had compared the survival outcomes of Lob and Sub-lob in varying extent degrees of pleural infiltration. Choi et al. and Wo et al.    [14]. Contrary to the studies mentioned above, Moon et al. investigated the surgical outcomes of 271 NSCLC patients with PL, indicating that the survival rate did not differ considerably depending on the extent of surgery [15]. The current study demonstrated that Lob was a favorable factor in low CSD before and after PSM compared with those treated with Sub-lob. Several potential mechanisms may explain the benefit of survival outcomes from larger extent radical surgeries. Firstly, PL is correlated with a high incidence of lymph nodes metastasis [13,22]. Kudo et al. discovered that the visceral pleura was densely packed with lymphatic vessels, with an interconnected network extending over the lung surface, The lymphatic vessels penetrated the lung parenchyma to connect bronchial lymph vessels with drainage to numerous hilar Lymph nodes [23]. Imai et al. indicated that lymphatic vessels beneath the pleura  might flow directly into the mediastinum without going through the hilar Lymph nodes, resulting in skip N2 metastases [24]. Moreover, previous studies illustrated that more lymph nodes dissected in surgically resected NSCLC could improve the survival rate [25,26]. Compared with Sub-lob, Lob, which tends to perform more comprehensive lymph nodes excision and obtain R0 resection, is associated with a better prognosis among NSCLC patients with PL [13,22]. Secondly, Sub-lob can easily impair the lymph nodes' integrity and disrupt the drainage system, resulting in decreased lymphatic fluid release during segmental lymph nodes dissection. Finally, regardless of how carefully a Sub-lob of NSCLC is performed, the possibility of cancer cells at the surgical margin remains, which is associated with locoregional recurrence and a poor prognosis [27,28]. Interestingly, in the subgroups analyses, only the patients in the PL-2 cohort presented significantly different survival outcomes, indicating lower CSD in the cases that underwent Lob. In surgically resected NSCLC, the poor prognostic impact of PL has been clearly outlined. Nevertheless, the prognostic significance of the PL depth, especially in PL-1 and PL-2, was still under debate. Some [29][30][31][32][33] but not all studies [34][35][36] confirmed that resected NSCLC patients with PL-2 had a significantly worse prognosis, frequent recurrence [31], and pleural dissemination [33] contrast with PL-1. A high level of PL was commonly associated with increasingly aggressive biological characteristics. Kondo et al. reported that the pleural lavage cytology was positive in 13 of 96 (14%) and 15 of 41 (37%) patients in the PL-1 and PL-2 groups [37]. However, the above studies did not carry out the prognostic outcomes of PL depth between different surgical operations. As previous research mentioned, Lob could achieve more extensive lymphatic clearance and reduce the possibility of cancer cells remnant. And PL-2 patients tended to show the characteristics of local lymph node metastasis and recurrence. We supported the view that in NSCLC patients, PL depth should be considered in selecting the optimal surgery type. Conventional preoperative diagnostic methods were limited in diagnosing PL. However, with the exploration of new technology such as circulating tumor cells combined with CT features, and artificial-intelligence CT texture features, a more accurate preoperative judgment of PL may be realized [38,39].
This study comprehensively compared the CSD of Lob and Sub-lob in the NSCLC patients with PL. Meanwhile, a relatively accurate and discriminating nomogram was developed and internally validated. Based on the competing risk analysis, the model incorporated age, gender, grade, T stage, N stage, metastasis, pleural invasion, surgery, radiation, and chemotherapy. It was reported that age and grade were closely related to prognosis in NSCLC [32,40]. And the model showed that patients who underwent Sub-lob were associated with an increased risk for CSD. The reasons have been discussed in the previous paragraphs. Higher extent of PL was also correlated with more CSD probability. It was reported that malignant tumor cells have increasingly aggressive and progressive biological characteristics with the increasing level of PL and contribute to adverse outcomes for the patients [32]. The advantage of nomogram over standard multivariate regression model was providing the individual probability of 1-, 3-, 5-year CSD instead of a relative risk concept. The listed factors can be easily obtained from clinical and pathological data. Besides, our nomogram presented favorable potential clinical applicability and could contribute to patient counseling, follow-up scheduling, and treatment selection.
However, several limitations that existed in the current study should raise attention. Firstly, the SEER data repository lacked some pivotal factors tied to prognosis, including smoking history, comorbidities, and genetic records of patients. Secondly, as a retrospective analysis, although PSM was used to minimize the heterogeneity between the groups, selection bias was inevitably brought in. Despite these limitations, the large cases could provide novel insights into the surgical treatment in PL NSCLC patients.

Conclusion
Our findings supported that Lob should be considered the preferred surgery in contrast with Sub-lob for NSCLC patients with PL. A prognostic nomogram was constructed and validated to predict the individualized probability of CSD at 1-, 3-and 5-year, which presented excellent prediction ability for these patients. External and prospective validation was required for widely applying.